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Correction: DOR/Tp53inp2 and Tp53inp1 Constitute a Metazoan Gene Family Encoding Dual Regulators of Autophagy and Transcription

Ana Sancho,Jordi Duran,A. García-España,Caroline Mauvezin,E. A. Alemu,T. Lamark,M. Macias,R. DeSalle,M. Royo,D. Sala,J. Chicote,M. Palacín,T. Johansen,A. Zorzano

Published 2012 in PLoS ONE

ABSTRACT

Human DOR/TP53INP2 displays a unique bifunctional role as a modulator of autophagy and gene transcription. However, the domains or regions of DOR that participate in those functions have not been identified. Here we have performed structure/function analyses of DOR guided by identification of conserved regions in the DOR gene family by phylogenetic reconstructions. We show that DOR is present in metazoan species. Invertebrates harbor only one gene, DOR/Tp53inp2, and in the common ancestor of vertebrates Tp53inp1 may have arisen by gene duplication. In keeping with these data, we show that human TP53INP1 regulates autophagy and that different DOR/TP53INP2 and TP53INP1 proteins display transcriptional activity. The use of molecular evolutionary information has been instrumental to determine the regions that participate in DOR functions. DOR and TP53INP1 proteins share two highly conserved regions (region 1, aa residues 28–42; region 2, 66– 112 in human DOR). Mutation of conserved hydrophobic residues in region 1 of DOR (that are part of a nuclear export signal, NES) reduces transcriptional activity, and blocks nuclear exit and autophagic activity under autophagy-activated conditions. We also identify a functional and conserved LC3-interacting motif (LIR) in region 1 of DOR and TP53INP1 proteins. Mutation of conserved acidic residues in region 2 of DOR reduces transcriptional activity, impairs nuclear exit in response to autophagy activation, and disrupts autophagy. Taken together, our data reveal DOR and TP53INP1 as dual regulators of transcription and autophagy, and identify two conserved regions in the DOR family that concentrate multiple functions crucial for autophagy and transcription. Citation: Sancho A, Duran J, Garcı́a-España A, Mauvezin C, Alemu EA, et al. (2012) DOR/Tp53inp2 and Tp53inp1 Constitute a Metazoan Gene Family Encoding Dual Regulators of Autophagy and Transcription. PLoS ONE 7(3): e34034. doi:10.1371/journal.pone.0034034 Editor: Orian S. Shirihai, Boston University, United States of America Received October 21, 2011; Accepted February 21, 2012; Published March 28, 2012 Copyright: 2012 Sancho et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: JD was an FPI Fellow and AS is an FIS Fellow at the ‘‘Instituto de Salud Carlos III’’, Spain. This study was supported by research grants from the MEC ‘‘Ministerio de Educación y Ciencia’’ (SAF2008-03803), Grant 2009SGR915 from the ‘‘Generalitat de Catalunya’’, CIBERDEM (‘‘Instituto de Salud Carlos III’’), (INTERREG IV-B-SUDOE-FEDER (DIOMED, SOE1/P1/E178), and COST Action BM0602 to A.Z., from the Norwegian Research Council and Norwegian Cancer Society to T.J, and PI070789 from ‘‘Instituto de Salud Carlos III’’ to AGE. AGE is supported by the Research Stabilization Program of the Instituto de Salud Carlos III-Institut Català de la Salut in Catalonia. AZ is the recipient of a Science Intensification Award from the University of Barcelona. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Rob DeSalle is a PLoS ONE Editorial Board member. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: antonio.zorzano@irbbarcelona.org

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